Vitamin D, 1,25 dihydroxycholecalciferol (calcitriol) has significant antiproliferative activity in vivo and in vitro. Calcitriol induces G0/G1 arrest, modulates p27 and p21, induces cleavage of caspase 3, MEK, and PARP, inhibits P-Akt and significantly increases MEKK-1. In vitro and in vivo, dexamethasone (dex) potentiates calcitriol-mediated antitumor activity through the vitamin D receptor (VDR). In a phase II trial in androgen-independent prostate cancer (AIPC) with high dose oral calcitriol and dex, we observed a 50 percent reduction in serum prostate specific antigen (PSA) in 28 percent of patients. Also, calcitriol significantly enhances the in vitro and in vivo antitumor efficacy of platinum analogues and taxanes. Enhancement of drug-mediated apoptosis by calcitriol is associated with an increase in PARP-, MEK- and caspase-cleavage, p73 and MEKK-1 with a decrease in P-Erk and P-Akt. Thus, we performed two phase I trials of calcitriol with either carboplatin or paclitaxel. From the pharmacokinetic (pk) data, increasing oral doses of calcitriol did not result in higher serum calcitriol levels; suggesting a potential decrease in bioavailability. In addition, calcitriol increases the expression of EGFR. When calcitriol is combined with the EGFR tyrosine kinase inhibitor, ZD 1839 ('Iressa'), a significant enhancement of antitumor activity is observed in vitro and in vivo associated with a significant decrease in P-Erk and P-Akt. Therefore, calcitriol has significant pro-apoptotic effects and can synergize with other cytotoxic modalities that potentially share the targets, P-Akt, P-Erk, MEKK-1 and/or p73. Therefore, we propose to examine the potential efficacy and mechanisms of calcitriol in combination with cytotoxic agents both clinically and pre-clinically by the following specific aims: 1) to determine the modulation of the molecular events of apoptosis in the calcitriol signaling pathway by platinum and taxanes in vitro and in vivo in tumor models; 2) to evaluate high dose intravenous (iv) calcitriol (QDx2, D1, 2), docetaxel (70mg/m 2, D2) and dex (QDx2, D1, 2) every 21 days in AIPC in a phase I/II clinical trial; 3)to determine the mechanisms involved in the enhanced antitumor activity of the tyrosine kinase inhibitor, ZD 1839 in combination with calcitriol in vitro and in vivo and 4) to examine in the Phase I setting ZD1839 250mg,QD) with escalating high iv doses of calcitriol weekly in patients with advanced cancer